The United States government has rights in this invention by virtue of National Institute of Health grant No. GM25810.
Hydroxamic acids are known for their special ability to form complexes with heavy metals, particularly iron(III). The intense colors and the high stabilities of many of these complexes have led to the development of various analytical procedures based upon these reactions. A number of hydroxamic acids also show biological activity, such as urease inhibition and anticoagulant activity.
Although the literature on hydroxamic acids is extensive and the chemistry well defined, there is little concerning polymers bearing hydroxamic acid groups.
In one case, vinyl monomers bearing hydroxamic acid groups were reported to polymerize under a variety of conditions. The monomers acrylo-, methacrylo-, crotono-, and cinnamohydroxamic acids were prepared by reaction of the corresponding ester with hydroxylamine. In a second case, however, Becke and Mutz, Chem. Rev., 98,1322 (1965), reported an unsuccessful attempt to prepare acrylohydroxamic acid from ethyl acrylate due to competing Michael addition. Use of the acid chloride was successful, but with only an 8% yield of pure monomer. M. Narita et al.in Bull. Chem. Soc.Japan, 45,3149 (1972) reported the preparation of methacrylohydroxamic acid from the ester, but found that the monomer resisted attempts at copolymerization with styrene-divinylbenzene.
In other reports, the hydroxamic acid group is generated on or added to preformed polymers of various kinds. U.S. Pat. No. 2,402,604 discloses treatment of maleic anhydride copolymers with hydroxylamine, as does Cocea et al. in Bul.Inst.Politeh.Iasi 11,159 (1965) Chem.Abst. 64 19800a (1966). Various groups have also used the treatment of polyacrylonitrile with hydroxylamine followed by hydrolysis of the intermediate amidoxime, yielding, in part, pendant hydroxamic acid groups, for the metallation of acrylic fabrics.
Ion exchange resins based upon the hydroxamic acid groups have been prepared from Amberlite IRC-50 by conversion of the carboxyl groups to the acid chloride or to the ester, followed by treatment with hydroxylamine. Used in a column, the modified resin shows a significant increase in the retardation of various metal ions. The acid chloride method has also used by M. Vrancken and G. Smets in J.Polym.Sci., 14,521 (1954) by treating poly (acryloyl chloride) with hydroxylamine in dimethylformamide. The copolymerization of various hydroxamic acid-substituted phenols and catechols into phenolic resins has been reported to give a fairly selective ion exchange resin for heavy metals.
The reaction of esters with hydroxylamine, normally a standard procedure for preparing hydroxamic acids, has been used by M. Narita et al, Bull.Chem.Soc Japan 45,3149 (1972); by W. Kern and R. C. Schultz, Angew Chem. 69, 153, (157); and by M. Hatano et al in Kogyo Kagakev Zasshi 69, 571 (1966) and Chem Abstr. 65, 15532g (1966), in a number of instances, with mixed results, for preparing polymers. Of particular note is the work of Kern and Schultz, who, through reaction of poly(methylacrylate) with hydroxylamine, reported a polymer containing 80% acrylohydroxamic acid, 14% acrylic acid, and 6% methyl acrylate, and which formed the characteristic red-brown iron(III) complex. The ratio of hydroxamic acid to iron in the complex was found to be 3:1.
In other reports, styrene-divinylbenzene copolymers containing ethyl acrylate or the active esters p-nitrophenyl acrylate or p-nitrophenyl methacrylate either failed to react with hydroxylamine or resulted in polymers containing a considerable fraction of carboxyl groups. However, hydroxamic acid polymers could be prepared through reaction of the active ester substituted polymer with 0-benzylhydroxylamine followed by treatment with hydrogen bromide.
In searching for polymeric chelating agents for treating cases of extreme iron poisoning, the trihydroxamic acid, deferoxamine-B, has been grafted to several polymers through reaction at the free amine group.
Vernon et al in Anal.Chim.Acta 72,331(1974); 77,145 (1975); 79,229 (1975); 82,369 (1976) and 83,187 (1976) described the preparation and applications of poly(hydroxamic acids)s. The preferred synthesis route was partial hydrolysis of macroporous acrylonitrile divinylbenzene copolymer, followed by hydroxylaminolysis. These resins are used for the separation of metal ions and recovery of uranium from synthetic sea water. A. Winston and E. T. Mazza in J.Polym.Sci.Polym.Chem.Ed. 13,2019(1975) and 14,2155(1976) studied the effect of the spacing of hydroxamic acid units in a polymer on its affinity to iron ions. Poly(hydroxamic acid)s were synthesized from acryloyl chloride and B-alanine or from poly(acrylic acid).
R. Phillips and J. S. Fritz in Anal.Chim.Act, 121, 225 (1980) synthesized an N-phenylhydroxamic acid resin by attaching N-Phenylhydroxamic acid units to Amberlite XAD-4. The use of poly(acrylonitrile) for the synthesis of poly(hydroxamic acid) was also reported by A. Shah and S. Devi in Analyst 110,1501, (1981). The polymer was used for the separation of lead and copper from aqueous solutions.
U.S. Pat. No. 4,536,296 to Vio discloses using drilling mud with low viscosity and stability at temperatures of up to 200.degree. C. which contains one to ten grams low molecular weight (preferably 10,000) polymer or copolymer having hydroxamic or thiohydroxamic functional groups. The polymers are prepared by polymerization of a vinyl monomer having a hydroxamic or thiohydroxamic functional group alone or in combination with another vinyl monomer at a temperature between about 50.degree. and 110.degree. C. in the absence of oxygen, at a pH of less than 7, for between 0.5 and 20 hours. European Pat No. 0 104,970 to Societe National Elf Aquitaine (Vio and Meunier) discloses a similar method for making drilling mud wherein an aqueous solution of polyacrylamide is reacted at a temperature between 50.degree. C. and 85.degree. C.
Despite the variety of suggested polymers and applications, no one has ever disclosed, nor even suggested, a method using primary amide polymers, such as poly(acrylamide)s, as starting materials for the synthesis of hydroxamic acid polymers where the polymers are reacted with hydroxylamines at low temperature under basic conditions to yield a polymer containing low concentrations of carboxylic acid groups, in addition to the major content of hydroxamic acid groups.
It is therefore an object of the present invention to provide a method to produce polymers having a predominance of hydroxamic acid groups and a very low percentage of carboxylic groups which are relatively inert and biocompatible.
It is a further object of the present invention to provide a method to produce polymers which are biologically active.
It is a still further object of the present invention to provide a method to produce polymers which have high affinity for metal ions and a rapid reaction rate.